The long range objective of the proposed research is an understanding of the molecular basis of the pharmacological effects of morphine and related narcotic analgesics, including analgesia and the development of tolerance and physical dependence. The recent discovery of stereospecific opiate receptors in animal and human brain open up research approaches which should aid in the attainment of this goal. Our major efforts will be concerned with the study of narcotic receptors and their interactions with agonists and antagonist drugs. Attempts will be made to discover biochemical events, triggered by opiate-receptor binding, which lead to the observed pharmacological responses. The effects of tolerance and physical dependence on biochemical pathways and the level and properties of receptors will be investigated. An organotypic culture system sensitive to opiate has been developed as a model system useful for many of the proposed studies.